In the brain, resolvins (E- and D-series), maresins and protectins/neuroprotectin D1 work as an endogenous “finish line” program that calms neuroinflammation while safeguarding synaptic function, barrier integrity and repair. Microglia, astrocytes, endothelial cells and neurons produce and respond to these DHA/EPA-derived mediators via specific G-protein–coupled receptors. RvD1 signals through FPR2 and (in humans) GPR32; RvD2 engages GPR18; RvE1 activates ERV1 while MaR1 activates LGR6; and recent work identifies GPR37 as a receptor for neuroprotectin D1 (NpD1). Receptor activation restrains NF-κB and MAPK inflammatory transcriptional programs, elevates cAMP/PKA and ERK in a temporally tuned fashion, optimizes mitochondrial respiration and reprograms cytoskeletal dynamics to boost phagocytosis/efferocytosis of debris and amyloid while limiting neutrophil/monocyte recruitment to the parenchyma.
In glia, SPMs push microglia away from a chronically reactive state toward pro-resolving, synapse-supportive phenotypes; in astrocytes they temper reactive astrogliosis and restore glutamate and potassium homeostasis; at the neurovascular unit they tighten endothelial junctions and reduce leukocyte–endothelium adhesion, stabilizing the blood–brain barrier (BBB). Notably, SPM signaling also operates through regulatory microRNAs and chromatin programs—for instance, RvD1-FPR2 drives microRNA circuits that halt remote neuroinflammation after focal brain damage, while MaR1–LGR6 signaling activates a CREB→JMJD3→IRF4 axis that dampens neuroinflammation after subarachnoid hemorrhage. NPD1 signaling via GPR37 promotes phagocytosis and cytoprotection, linking resolution to neuronal survival. Across pathophysiology, an inadequate or delayed resolution response is a recurring feature.
In Alzheimer’s disease brains and cerebrospinal fluid, SPM profiles are dysregulated with compensatory up-ticks in some receptors and biosynthetic enzymes, yet overall resolution tone appears insufficient: microglial clearance of amyloid is suboptimal, astrocytes remain reactive and BBB leak persists; experimental SPM provision improves microglial amyloid uptake and restrains cytokine cascades. In traumatic and ischemic brain injury models, RvD1 via FPR2 curbs secondary waves of neuroinflammation and improves functional recovery, while NPD1 and MaR1 limit neuronal death and glial overactivation. In autoimmune demyelination (EAE), MaR1 restores immune–glial metabolic balance and reduces pathology, and in broader neurodegenerative contexts, consensus statements emphasize SPMs’ ability to cross the BBB, quell microglial activation and lower inflammation without immunosuppression.
Collectively, human and experimental data point to resolution failure—not merely inflammation excess—as a shared axis of disease maintenance in the CNS. Enhancing the brain’s resolving response can be approached at three complementary levels. First, bolster substrate and biosynthesis: providing marine omega-3s (EPA/DHA) increases circulating SPMs and SPM-pathway intermediates in randomized trials, reprogramming immune responses toward resolution; in mild cognitive impairment, omega-3 supplementation has been associated with higher RvD1 and improved Aβ phagocytosis by patient monocytes. Low-dose aspirin uniquely acetylates COX-2 to generate “aspirin-triggered” D-series resolvins and protectins (17R-epimers), a route that has shown neuroprotective effects in perioperative neurocognitive models and may extend to other neuroinflammatory states.
Second, deliver resolution agonists directly: preclinical CNS studies demonstrate benefits of intranasal or central administration of RvD1, NPD1 analogs and MaR1—routes that exploit nose-to-brain pathways while minimizing systemic exposure. Third, target receptors and downstream programs: amplifying FPR2, ERV1, LGR6 or GPR37 signaling—or the CREB/JMJD3 chromatin axis they control—offers druggable nodes to restore efferocytosis, normalize microglial metabolism and reseal the blood-brain barrier. While standardized lipidomic endpoints and dose-finding in rigorously powered trials are still needed, these strategies aim to complete—rather than suppress—the inflammatory response in the brain.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Scientific references
Xu J et al. Pharmacol Res. 2025 Jun; 216:107746.
Serhan CN et al. FASEB J. 2024 May; 38:e23699.
Sun S et al. Front Immunol. 2024; fimmu1444740.
Ghemiș L et al. Biomedicines. 2024; 25(23):12784.
Julliard W et al. Front Immunol. 2022; 59:101605.
Tiberi M et al. Front Cell Neurosci. 2021; 15:673549.
Li C et al. Front Pharmacol. 2020; 11:2020.00612.
Souza PM et al. Circ Res. 2020 Jan; 126(1):75-90.
